Numerous meta-analyses have identified various risk factors for hepatocellular carcinoma (HCC), prompting a comprehensive study to synthesize evidence quality and strength.

This umbrella review of meta-analyses was conducted throughout PubMed, EMBASE, Web of Science, and Cochrane Database of Systematic Reviews. Evidence strength was evaluated according to the evidence categories criteria.

We identified 101 risk factors throughout 175 meta-analyses. 31 risk factors were classified as evidence levels of class I, II, or III. HBV and HCV infections increase HCC risk by 12.5-fold and 11.2-fold, respectively. These risks are moderated by antiviral treatments and virological responses but are exacerbated by higher HBsAg levels, anti-HBc positivity, and co-infection. Smoking, obesity, non-alcoholic fatty liver disease, diabetes, low platelet, elevated liver enzymes and liver fluke infection increase HCC risk, while coffee consumption, a healthy diet, and bariatric surgery lower it. Medications like metformin, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), aspirin, statins, and selective serotonin reuptake inhibitors reduce HCC risk, while acid suppressive agents, particularly proton pump inhibitors, elevate it. Blood type O reduces the risk of HCC, while male gender and older age increase the risk.

HBV and HCV are major HCC risk factors, with risk mitigation through antiviral treatments. Lifestyle habits such as smoking and alcohol use significantly increase HCC risk, highlighting the importance of cessation. Certain drugs like aspirin, statins, GLP-1 RAs, and metformin may reduce HCC occurrence, but further research is needed to confirm these effects.

Hepatocellular carcinoma (HCC), which accounts for about 90% of all primary liver cancer cases, is the fifth most common malignancy and the second leading cause of cancer-related mortality worldwide. This study aims to analyse the differential costs of HCC-related hospital admissions compared to the general population in Spain.

A retrospective multicenter study analyzed inpatient admissions from a Spanish national discharge database, covering 90% of hospitals between 2010 and 2022. HCC-related admissions were identified using ICD-9 and ICD-10 codes, while control admissions were selected from the general population in the same database without an HCC diagnosis. The direct hospitalization cost was included, covering medical examinations, procedures, medications, surgeries, personnel and equipment. Statistical methods, including nearest-neighbor matching, propensity score matching, and a generalized linear model, were used to estimate differential costs and to ensure comparability based on age, gender, and Charlson Comorbidity Index (CCI).

A total of 199,670 HCC-related hospital admissions and 200,000 control admissions were analyzed. Most HCC-related admissions involved male patients (78%) aged 66-85 years, with an average CCI of 5.18. HCC-related admissions incurred significantly higher costs, with an estimated differential cost of €1,303.68 using GLM, €1,804.25 via propensity score matching, and €1,767.77 using nearest-neighbor matching. Total costs per HCC admission ranged between €1,000 and €31,000.

HCC-related hospital admissions impose a significantly higher economic burden due to the complexity of care. Given the high mortality and resource utilization, advancements in early detection, treatment, and cost-effective interventions are needed to improve patient outcomes and reduce healthcare costs.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the major causes of chronic liver disease among adolescents. However, epidemiological studies on MASLD in adolescents are still insufficient. In this study, we aim to investigate the global burden and the trend of MASLD in adolescents from 1990 to 2021.

The age-standardized incidence, prevalence, mortality, and disability-adjusted life years (DALYs) of MASLD were calculated based on the Global Burden of Disease (GBD) 2021 study and stratified by sex, socio-demographic index (SDI), GBD regions, and countries. The temporal trends were examined using the average annual percentage change (AAPC) and joinpoint regression.

From 1990 to 2021, the global trends of age-standardized incidence rate (ASIR) and age-standardized prevalence rate (ASPR) of MASLD show notable increase, and the male is significantly higher than the female in adolescents. According to the incidence and prevalence, nations with low SDI confront a higher burden of MASLD. Besides, the inequality of incidence and prevalence between different SDI regions have shrunk in 2021, but the inequality of DALYs and mortality are still exacerbated. Decomposition analysis revealed that population growth and epidemiological changes were the main reasons for the increase in the incidence of MASLD.

From 1990 to 2021, there is a significant upward trend in the incidence of MASLD among adolescents worldwide. Of particular note are male adolescents, East Asian regions, and groups living in high SDI countries.

Noninvasive assessment of liver fat content is crucial due to the high global prevalence of nonalcoholic fatty liver disease. Algorithms based on ultrasound (US) attenuation coefficient (AC) for estimating liver fat content are commercially available, but a lack of consensus exists regarding the best estimation protocol. The aim of our study was to evaluate the influence of the size of the region of interest (ROI) on the US AC.A prospective study was conducted. An abdominal US was done for 86 outpatients. A sampling box was positioned within the liver parenchyma, approximately 2 cm beneath the liver capsule with a ROI, measuring about 2 × 4 cm and then 4 × 5 cm, precisely placed at the center of this sampling box. Five readings of the AC were captured, and the average of these measurements was employed to assess the severity of hepatic steatosisA statistically significant difference between AC with 2 different ROI sizes was shown (P < 0.001) with AC values with 2 × 4 cm ROI were higher than those obtained with 4 × 5 cm ROI (AC mean 0.668 VS 0.653). However, the agreement between AC values obtained with 2 different ROI sizes was excellent (correlation coefficient 0.941)An ROI size dependence is observed in the measurement of AC in the liver. A standardized acquisition protocol with a fixed size of the ROI needs to be developed to minimize differences in AC measurements and to assess changes in serial measurements reliably.

The continuum of metabolic syndrome encompasses a spectrum of dysfunctions impacting obesity-linked insulin resistance, glucose homeostasis, lipid metabolism and pro-inflammatory immune responses. The global prevalence of metabolic diseases, including diabetes, chronic liver disease, cardiometabolic disease and kidney disease, has surged in recent decades, contributing significantly to population mortality. Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, is a leading cause of liver disease worldwide. MASLD poses a significant global health challenge with its rising prevalence, placing a substantial burden on healthcare systems, impacts patient well-being and incurs significant economic costs. Addressing MASLD requires a comprehensive understanding of its interconnected factors, including its prevalence, healthcare burden and economic implications. Lack of awareness, imprecise non-invasive diagnostic methods and ineffective preventive interventions are core components of the MASLD-related problem.

The aim of this article was to summarise the global burden of MASLD from the payer's perspective.

We carried out a review of the global comprehensive burden of MASLD. These topics led to discussions and insights by an expert panel during the 7th Metabolic Continuum Roundtable meeting, which took place in November 2023. This meeting focused on the burden, patient-reported outcomes and health economics, from payor and societal perspectives, and aimed to identify opportunities for improving patient care, optimise resource allocation and mitigate the overall impact on individuals and society related to MASLD. During the roundtable, an emphasis emerged on the need for greater awareness and strategic deployment of diagnostic, therapeutic and preventative measures to address MASLD effectively.

The global burden of MASLD is high and growing. Prioritising the prevention of metabolic dysregulation and timely therapeutic interventions can yield a holistic strategy to combat MASLD, its progression and potentially lower disease costs.

NCT06309992.

Clinically significant posthepatectomy liver failure (PHLF B+C) remains the main cause of mortality after major hepatic resection. This study aimed to establish an aspartate aminotransferase to platelet ratio combined with an albumin-bilirubin grade (APRI+ALBI), based multivariable model (MVM) to predict PHLF and compare its performance to indocyanine green clearance (ICG-R15 or ICG-PDR) and albumin-ICG evaluation (ALICE).

A total of 12,056 patients from the National Surgical Quality Improvement Program database were used to generate a MVM to predict PHLF B+C. The model was determined using stepwise backwards elimination. The performance of the model was tested using receiver operating characteristic curve analysis and validated in an international cohort of 2525 patients. In 620 patients, the APRI+ALBI MVM, trained in the National Surgical Quality Improvement Program cohort, was compared with the MVM's based on other liver function tests (ICG clearance, ALICE) by comparing the areas under the curve (AUC).

A MVM including APRI+ALBI, age, sex, tumor type, and extent of resection was found to predict PHLF B+C with an AUC of 0.77, with comparable performance in the validation cohort (AUC: 0.74). In direct comparison with other MVM's based on more expensive and time-consuming liver function tests (ICG clearance, ALICE), the APRI+ALBI MVM demonstrated equal predictive potential for PHLF B+C. A smartphone application for the calculation of the APRI+ALBI MVM was designed.

Risk assessment through the APRI+ALBI MVM for PHLF B+C increases preoperative predictive accuracy and represents a universally available and cost-effective risk assessment before hepatectomy, facilitated by a freely available smartphone app.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) are the major contributors to the liver disease burden globally. The rise in these conditions is linked to obesity, type 2 diabetes, metabolic syndrome and increased alcohol consumption. MASLD and ALD share risk factors, pathophysiology and histological features but differ in their thresholds for alcohol use, and the ALD definition does not require the presence of metabolic dysfunction. A recent multi-society consensus overhauled the nomenclature of liver steatosis and introduced the term MetALD to describe patients with metabolic dysfunction who drink more than those with MASLD and less than those with ALD. This new terminology aims to enhance the understanding and management of liver disease but poses challenges, such as the need to accurately measure alcohol consumption in research and clinical practice settings. Recent studies show that MetALD has significant implications for patient management, as it is associated with increased mortality risks and more severe liver outcomes compared to MASLD alone. MetALD patients face increased risks of liver disease progression, cancer and cardiovascular disease. The diagnosis of MetALD involves the adequate quantification of alcohol use through standardised questionnaires and/or biomarkers as well as proper assessment of liver disease stage and progression risk using non-invasive tools including serologic markers, imaging, elastography techniques and genetic testing. Effective management requires addressing both metabolic and alcohol-related factors to improve outcomes. This review intends to provide a comprehensive overview of MetALD, covering pathogenesis, potential diagnostic approaches, management strategies and emerging therapies.

Disulfiram, a synthetic drug, has historically played a significant role in the treatment of alcoholic liver disease as the first medication approved by the U.S. Food and Drug Administration for alcohol use disorders. Beyond its efficacy in inhibiting alcohol addiction and treating alcoholic liver disease, disulfiram has also demonstrated potential in managing various liver conditions, including certain metabolic liver injuries and liver cancer. As an established, cost-effective drug with well-documented synthesis methods, disulfiram holds promise for broader application in liver disease treatment. However, its clinical use is hindered by the risk of inducing pharmacologic liver injury. This potential for liver toxicity necessitates careful patient selection, monitoring, and consultation with healthcare providers, which can limit its practicality in treating patients with existing liver conditions. This review aims to analyze the multifaceted role of disulfiram in liver diseases comprehensively. By exploring its therapeutic efficacy, potential benefits, and inherent limitations, we seek to provide a balanced perspective that maximizes disulfiram's therapeutic potential while ensuring the safety and well-being of patients. This thorough examination will also highlight areas for future research, paving the way for optimized treatment protocols that incorporate disulfiram in the context of liver disease management.

Metabolic-dysfunction associated steatotic liver disease (MASLD) is associated with prevalent cardiovascular disease. More favorable cardiovascular health (CVH) profiles are associated with a lower prevalence of MASLD in cross-sectional studies. The relationship between long-term CVH patterns and MASLD prevalence in midlife remains unknown.

Participants (aged 18-30 years at baseline) of the CARDIA (Coronary Artery Risk Development in Young Adults) study who had individual CVH components measured at 7 examinations over 20 years and liver fat assessed by noncontrast computed tomography at year 25 follow-up were included. CVH score was defined using published American Heart Association definitions. Group-based trajectory modeling was used to identify CVH trajectories. MASLD was defined as liver attenuation of ≤51 Hounsfield units with at least 1 metabolic risk factor after excluding other causes of liver fat. Logistic regression was used to examine associations of CVH trajectory groups and MASLD prevalence. At baseline, 39% of 2529 participants had high and 5% had low CVH, respectively. MASLD prevalence at year 25 was 23% (n=587). Five distinct CVH trajectories were identified. Between the 2 groups that started at similar CVH scores, those whose CVH declined over time had a higher prevalence of MASLD at year 25 (7.0% in high-stable versus 23.0% high-decreasing; 24.4% in moderate-stable versus 35.7% in moderate-decreasing). Lower and decreasing trajectories were associated with higher year-25 MASLD prevalence compared with the high-stable trajectory.

Achieving and maintaining high CVH scores starting in young adulthood lowers the risk of prevalent MASLD in midlife.

It has been reported that periodontitis was a risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD). The aim of this study is to investigate the impact of periodontitis on all-cause and cause-specific mortality of MASLD patients.

We included 11,019 individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) from the National Health and Nutrition Examination Survey. Multivariable Cox proportional hazards models were utilized to analyze the estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality and cause-specific mortality among participants with different periods of periodontitis status. Additionally, we employed restricted cubic splines (RCS) curves to explore the dose-response relationship between clinical attachment level (CAL) and pocket probing depth (PPD) and mortality rates. Finally, a series of sensitivity analyses and stratification analyses were conducted to test the reliability and robustness of the results.

In this study, moderate to severe periodontitis significantly increased the all-cause mortality (HR 1.29, 95% CI 1.08-1.55; P = 0.003) and cardiovascular disease (CVD)-related mortality (HR 1.41, 95% CI 1.10-1.79; P = 0.006) among MASLD participants. However, no significant effects of different periodontal statuses on cancer mortality were observed among MASLD participants.

A nationwide large-sample longitudinal study indicated that MASLD patients with moderate to severe periodontitis experienced significantly higher all-cause and CVD-related mortality rates compared to those with no or mild periodontitis.

The objective of this study was to examine the risks of cardiovascular events, incident type 2 diabetes (T2D), and mortality in patients with newly diagnosed metabolic dysfunction-associated steatohepatitis (MASH) compared with those without MASH in a large real-world setting in the US.

We retrospectively analyzed US claims data from Optum®'s de-identified Clinformatics® Data Mart database from October 2015 to December 2022. Patients with newly diagnosed MASH were matched 1:1 on age, sex, region, and index month-year with patients without MASH, and repeated for a subgroup without baseline diabetes. Risks of clinical outcomes associated with MASH were assessed using Cox proportional hazard models.

The study comprised 24,278 matched pairs in the patients with and without MASH cohorts. Patients with MASH had increased risks for any cardiovascular event (adjusted HR: 1.48 [95% CI = 1.38-1.58]), and all-cause mortality (1.31; 1.20-1.42) compared to those without MASH. For the subgroup without baseline diabetes (10,027 matched pairs), the adjusted HRs were 1.94 (95% CI = 1.68-2.23) for incident T2D and 1.40 (95% CI = 1.20-1.64) for all-cause mortality.

Our findings suggest increased risks of cardiovascular events, incident T2D, and mortality among patients newly diagnosed with MASH compared with patients without MASH.

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) can progress to end-stage liver disease and hepatocellular carcinoma (HCC), albeit infrequently in childhood. Our objectives were to (1) investigate the prevalence of elevated alpha-fetoprotein (AFP) in children with advanced, MASLD-related, fibrosis (bridging fibrosis or cirrhosis) and (2) ascertain whether pediatric MASLD is associated with AFP elevations regardless of fibrosis severity. Methods: Retrospective cohort study of patients aged 6-18 years seen at a single center between 2000 and 2024. Demographics, anthropometrics, blood work, histological data, and relevant imaging studies were collected. Descriptive statistics were used. Results: Out of a cohort of 483 pediatric patients followed for MASLD with available AFP data, 161 had undergone liver biopsy, and of those, 22 had advanced fibrosis. Children with advanced fibrosis were predominantly male (82%) and non-Hispanic (55%), with a median age of 11 years (interquartile range [IQR] = 10-18) and severe obesity (median [IQR] body mass index z-score 2.56 [2.33-2.75]). No patients with advanced fibrosis had elevated AFP levels. Of the entire MASLD cohort, however, nine had elevated AFP levels. None were diagnosed with HCC or other tumors. Conclusions: In a pediatric cohort with MASLD, severe fibrosis was not associated with elevated AFP levels. AFP elevations were seen however in some patients with MASLD but were not associated with malignancies.

Liver cancer is a significant global health concern, with projections indicating that the incidence of morbidity may surpass one million cases by 2025. Hepatocellular carcinoma (HCC) is the predominant subtype of liver cancer, constituting approximately 90% of all liver cancer diagnoses. Infections caused by the hepatitis B virus (HBV) and hepatitis C virus (HCV) are recognized as primary risk factors for the development of HCC. However, non-alcoholic steatohepatitis (NASH), which is often linked to metabolic syndrome or diabetes, is increasingly being recognized as a prevalent risk factor in Western populations. Furthermore, HCC associated with NASH exhibits distinct molecular pathogenesis. Patients diagnosed with HCC have access to a range of therapeutic interventions, including liver transplantation, surgical resection, percutaneous ablation, radiation therapy, and transarterial and systemic therapies. Consequently, effective clinical decision-making requires a multidisciplinary approach to adapt individualized treatment plans based on the patient's tumor stage, liver function, and overall performance status. The approval of new first- and second-line pharmacological agents, along with the establishment of immune checkpoint inhibitor therapies as standard treatment modalities, has contributed to an improved prognosis for patients with HCC. Nevertheless, the optimal sequencing of these therapeutic agents remains to be elucidated, highlighting the urgent need for predictive biomarkers to inform treatment selections. Traditional Chinese Medicine (TCM) has demonstrated potential as a complementary and alternative therapeutic approach for liver cancer, warranting further investigation. This review aimed to examine the comprehensive treatment of HCC through the lens of TCM, informed by the current understanding of its epidemiology, diagnosis, and pathophysiology.

A large number of patients with non-obese non-alcoholic fatty liver disease (NAFLD) in China remain undiagnosed and untreated due to insufficient awareness and ineffective pharmacotherapy. Therefore, a convenient, predictive marker and diagnostic tools are imperative. This study aimed to investigate the ability of the triglyceride glucose index (TyG) in predicting non-obese NAFLD.

An observational cross-sectional study.

Department of Health Management, large urban academic medical centre and DRYAD database data.

This study included 456 patients with non-obese NAFLD and matched 456 non-fatty liver controls according to age, sex and body mass index (BMI).

The receiver operating characteristic (ROC) curve was used to evaluate the predictive role of the TyG index in non-obese NAFLD. Based on the TyG index, a clinical prediction model for non-obese NAFLD was constructed, then the prediction model was verified by the DRYAD database (n=11 562).

TyG in non-obese NAFLD was higher than that in controls (9.00 (8.66-9.40) vs 8.46 (8.10-8.83), p<0.001). Logistic regression analysis showed that TyG was an independent risk factor for non-obese NAFLD (OR=9.03, 95% CI: 5.46 to 14.94, p<0.001). ROC analysis showed that the area under the curve (AUC) was 0.78, the sensitivity was 82.5%, the specificity was 60.5%. Based on the TyG index, sex, age and BMI, the AUC of the predictive model for non-obese NAFLD was 0.78 (95% CI: 0.75 to 0.81, p<0.001). Using the DRYAD database to verify the prediction model, the AUC of the verification group was 0.85 (95% CI: 0.84 to 0.86, p<0.001).

The high level of the TyG may be an independent risk factor for non-obese NAFLD. The prediction model for non-obese NAFLD based on the TyG index has good clinical prediction value.

To achieve a historical perspective, the chronological changes in primary liver cancer over a 20-year period were investigated at a single institution, focusing on shifts in etiology and the impact on imaging and pathological findings using The Liver Imaging Reporting and Data System.

A retrospective study of surgically resected primary liver cancer in 680 patients from 2001 to 2020 resulted in 434 patients with 482 nodules being analyzed. Dynamic contrast-enhanced computed tomography imaging and the Liver Imaging Reporting and Data System 2018 classification were employed. Two pathologists and two radiologists independently evaluated specimens and images.

This study highlighted a significant decline in cases of viral hepatitis and cirrhosis in primary liver cancer patients but an increase in intrahepatic cholangiocarcinoma and scirrhous hepatocellular carcinoma. Notably, there was a rise in non-viral hepatitis cases, potentially pointing toward an increase in steatohepatitic hepatocellular carcinoma cases in the future. Intrahepatic cholangiocarcinoma, scirrhous hepatocellular carcinoma and steatohepatitic hepatocellular carcinoma tumors exhibited slightly different distributions in the Liver Imaging Reporting and Data System classification compared with ordinary hepatocellular carcinoma, which may reflect the presence of fibrosis and lipid in tumor parenchyma.

Consistent with past reports, this study demonstrated the emergence of primary liver cancer against a backdrop of non-viral and non-cirrhotic liver. Liver Imaging Reporting and Data System has been consistently useful in diagnosing primary liver cancer; however, among the histological subtypes of hepatocellular carcinoma, an increase is anticipated in scirrhous hepatocellular carcinoma and steatohepatitic hepatocellular carcinoma, which may present imaging findings different from those of ordinary hepatocellular carcinoma. This development may necessitate a reevaluation of the current approach for diagnosing and treating hepatocellular carcinoma based solely on imaging.

This study aimed to explore the causal relationship between age at menarche (AAM) and non-alcoholic fatty liver disease (NAFLD), leveraging data from the 2017-2020 National Health and Nutrition Examination Survey (NHANES) alongside Mendelian randomization (MR) analyses. Notably, this research represents the first attempt to link AAM to NAFLD using genetic methodologies, thereby providing novel insights into the interplay between these two conditions.

Cross-sectional data from 2730 participants were analyzed using logistic regression to evaluate the association between AAM and NAFLD risk. A two-sample MR study was performed to investigate causal relationships, utilizing genetic data from large-scale genome-wide association studies (GWASs). The inverse variance weighted (IVW) method served as the primary MR analysis approach.

A significant negative association between AAM and NAFLD was found in Model 3 (OR = 0.85, 95 % CI: 0.74-0.97). Participants in the highest AAM quintile exhibited a 68 % reduction of NAFLD prevalence compared to those in the lowest AAM quintile (OR = 0.32, 95 % CI: 0.11-0.97). MR analysis confirmed a potential negative causal association (discovery: OR = 0.81, 95 % CI: 0.73-0.90; validation: OR = 0.80, 95 % CI: 0.66-0.96).

Our findings indicate a potential causal association between AAM and NAFLD, suggesting that early AAM may serve as a potential risk marker for NAFLD. This highlights the importance of incorporating AAM into clinical risk assessment tools and developing targeted prevention strategies for at-risk populations. Further research is needed to clarify the underlying mechanisms and to explore the potential benefits of early intervention.

Non-alcoholic steatohepatitis (NASH) is becoming a leading cause of liver disease in the US, while Rheumatoid arthritis (RA) affects a significant portion of the global population. In recent times, newer drugs have been developed to slow down the progression of RA, one of which is hydroxychloroquine (HCQ). Despite HCQ being linked to slowly progressive transaminitis, its role in the development of NASH remains unclear. Our research fills this gap by examining the prevalence and risk factors of developing NASH in patients with RA on HCQ.

This retrospective cohort study analyzed 619,350 adult patients diagnosed with RA. Data were sourced from a multicenter database covering over 360 hospitals across 26 healthcare systems in the US from 1999 to September 2022, excluding pregnant individuals. Multivariate regression analysis assessed the risk of NASH, adjusting for confounders including smoking history, male gender, dyslipidemia, hypertension, type 2 diabetes mellitus, obesity, and hydroxychloroquine use. Statistical significance was set at P<0.05, with analyses conducted using R version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria, 2008).

In a cohort of 79.4 million individuals, 619,350 non-pregnant subjects had rheumatoid arthritis, with 3,080 diagnosed with NASH, while 616,270 did not. Patients with NASH displayed a higher prevalence of smoking history, hyperlipidemia, hypertension, type 2 diabetes mellitus, obesity, and HCQ use. Multivariate regression analysis identified increased NASH risk in smokers (OR: 1.24; 95%CI: 1.14-1.36), males (OR: 0.88; 95%CI: 0.81-0.96), individuals with dyslipidemia (OR: 1.34; 95%CI: 1.21-1.47), hypertension (OR: 1.11; 95%CI: 1.00-1.27), type 2 diabetes mellitus (OR: 3.24; 95%CI: 2.98-3.54), obesity (OR: 3.59; 95%CI: 3.31-3.89), and hydroxychloroquine use (OR: 1.79; 95%CI: 1.65-1.94).

RA patients on HCQ showed an increased prevalence and odds of developing NASH, even after adjusting for common confounding factors. This indicates that HCQ may play a role in the development of hepatic steatosis and fibrosis. Clinicians should consider this association to prevent advanced liver disease. Future research should focus on optimal screening for early detection and enhancing patient outcomes.

• The study investigates the relationship between nonalcoholic steatohepatitis (NASH) and rheumatoid arthritis (RA), analyzing the impact of hydroxychloroquine (HCQ) use on the development of NASH.

• HCQ slows the progression of RA; however, its effect on the liver is not yet fully understood.

• This multicenter retrospective cohort study analyzed 619,350 adult patients diagnosed with RA.

• RA patients on HCQ showed an increased prevalence and higher odds of developing NASH. This association should be considered to prevent advanced liver disease.

The onset of decompensation in advanced chronic liver disease (ACLD) is a hallmark in natural history, with a poor prognosis and a significantly increased liver-related mortality. Etiological treatments for viral hepatitis or abstinence in cirrhosis due to alcohol abuse have demonstrated that some patients experience partial to complete clinical and analytical improvement, a stage termed "recompensation." Although recompensation is primarily defined clinically based on treatable etiologies, it is still evolving for conditions like metabolic dysfunction-associated steatotic liver disease (MASLD). Despite the need for specific biomarkers in hepatic recompensation, no biomarkers have been thoroughly studied in this context. Biomarkers identified in compensated ACLD (cACLD) following etiological treatment might be explored for recompensation. Although the pathophysiology mechanisms underlying the hepatic recompensation remain unclear, understanding the mechanism involved in cirrhosis decompensation could help identify potential targets for recompensation. This review provides an update on the hepatic recompensation concept, examines the existing data on invasive and non-invasive biomarkers, mainly in cACLD after cure, that could be raised in recompensation, and explores future therapeutic targets for the hepatic recompensation process.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most prevalent chronic metabolic diseases worldwide. While serum uric acid (SUA) and high-density lipoprotein cholesterol (HDL) are individually associated with the development of MASLD, the prognostic effect of the UA, HDL and SUA-to-HDL ratio (UHR) on the all-cause mortality of MASLD patients remains unexplored. This study utilized data from 4280 MASLD patients in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. UHR was calculated by dividing SUA by HDL, and its association with all-cause mortality was assessed using Cox proportional hazards models. Adjustments were made for demographic, lifestyle, and clinical factors. A one-standard-deviation increase in UA or UHR was associated with a 19% (HR 1.19, 95% CI 1.08-1.31, P < 0.001) or 18% (HR 1.18; 95% CI 1.07-1.30; P < 0.001) higher risk of all-cause mortality of MASLD participants respectively, while no association was found between HDL and mortality. SUA and UHR are promising predictors of all-cause mortality in MASLD patients, offering clinicians a valuable biomarker for related risk stratification. Its inclusion in clinical assessments could guide interventions and improve prognosis, advancing management for MASLD patients.

Metabolic associated fatty liver disease (MAFLD) is now a leading cause for chronic liver disease worldwide. Bariatric surgery has a beneficial effect on morbid obesity. We aimed at evaluating the impact of sleeve gastrectomy on the course of metabolic associated fatty liver disease.

An observational prospective cohort study from February 2021 to March 2023 included 66 morbidly obese patients diagnosed with MAFLD. Sleeve gastrectomy was done, where intra-operative liver biopsy was obtained. Baseline values of anthropometric measures, full metabolic profile and liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) using the XL probe were compared with three and six-months post-operatively.

Prevalence of MAFLD was histologically diagnosed in 75%. There was a significant decrease in body mass index, circumference, systolic and diastolic blood pressures in the low-density lipoprotein (LDL), triglycerides (TG), cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), LSM by transient elastography measurements in kilo Pascals (TE-kPa) and CAP level from baseline to three and six months post-operatively. Also, the AST/platelets ratio (APRI), NAFLD fibrosis score (NFS), fibrosis-4 (FIB-4) and atheroscelerosis cardiovascular risk score (ASCVD) scores decreased significantly from baseline to six months of follow-up. In MAFLD patients, there was a significant positive linear correlation between the CAP score and TE, between the CAP and AST, ALT, ASCVD score, but a negative correlation with high density lipoprotein (HDL). Also, there was a significant positive correlation between the percentage of decline TE and APRI scores and percentage of decline of CAP, glycated hemoglobin (HbA1c) and homeostasis model assessment for insulin resistance (HOMA-IR).

There was a very high prevalence of steatosis and steatohepatitis in asymptomatic morbidly obese patients. Sleeve gastrectomy has a beneficial effect on MAFLD and its associated comorbidities.

The MAESTRO-NASH phase 3 trial reported that a 52-week treatment of Resmetirom is effective in improving fibrosis and metabolic dysfunction-associated steatohepatitis (MASH) in patients with MASH and F2 or F3 fibrosis, while data on the impact on 5-year and long-term clinical outcomes are still lacking. We simulated the transition probabilities of disease progression in MASLD patients with F2 or F3 fibrosis and the effect of Resmetirom treatment on clinical outcomes.

A meta-analysis of literature data formed transition matrices for fibrosis stages and complications, defined as compensated (CC) and decompensated cirrhosis (DC), hepatocellular carcinoma (HCC) and mortality-liver-related mortality (LR-M), cardiovascular mortality (CV-M) and extra-hepatic cancer mortality (EHC-M). Markov model was developed to depict the F2 and F3 fibrosis stage progression towards the complications and to evaluate the effect of Resmetirom treatment on the natural history of MASLD.

We estimated the 5-year probability of Resmetirom-treated and untreated MASLD patients with baseline F2 fibrosis of developing CC (5.16% vs. 6.82%, respectively), DC (0.25% vs. 0.3%, respectively), HCC (0.25% vs. 0.32%, respectively) and mortality (0.15% vs. 0.16% for LR-M; 1.02% vs. 1.1% for CV-M; 1.07% vs. 1.2% for EHC-M, respectively). Similarly, we estimated the five-year probability of Resmetirom-treated and untreated MASLD patients with baseline F3 fibrosis of developing CC (17.12% vs. 21.34%, respectively), DC(1.1% vs. 1.47%, respectively), HCC (1.21% vs. 1.73%, respectively) and mortality (0.59% vs. 0.91% for LR-M, 1.92% vs. 2.14% for CV-M and 1.04% vs. 1.14% for EHC-M, respectively). Life Years Gained (LYG) of Resmetirom-treated patients were 0.45 and 0.63 in MASLD patients with F2 and F3 fibrosis, respectively, and the model was sensitive to changes in Resmetirom efficacy and transition probabilities.

Resmetirom decreases the 5-year and lifetime Markov-model estimated risk of CC, DC, HCC and liver-related mortality in patients with MASLD and F2 or F3 fibrosis.

The trend of alanine aminotransferase (ALT), a biomarker of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as nonalcoholic fatty liver disease), remains poorly described for the pediatric population because no widely accepted cutoffs are available to categorize ALT value. We described the nuanced changes in the distribution of ALT continuous values.

We analyzed the data from 15,702 adolescents aged 12-19 who participated in the National Health and Nutrition Examination Surveys between 1988 and 2020. The ALT distributions were standardized for age and sex. The prevalence of elevated ALT was also assessed.

The ALT geometric mean increased from 11.82 U/L in 1988-1994 to 17.24 U/L in 1999-2004, stayed above 17 U/L for a decade, and then decreased to 14.04 U/L in 2017-2020 (p for the quadratic trend <0.001). However, the 95th percentile of the ALT distribution remained above 35 U/L by the end of the study period after jumping from 26.02 U/L in 1988-1994 to 33.83 U/L in 1999-2004. The prevalence of elevated ALT (>42 U/L in boys and 30 U/L in girls), doubled from 1.53% (0.87%-2.19%) in 1988-1994 to 3.49% (2.73%-4.25%) in 1999-2004, and lingered around 4% through 2020.

The ALT mean decreased in recent years, but the prevalence of elevated ALT remained persistently high. Population-wide reductions in fructose consumption may have contributed to the decrease in ALT mean. The stagnant right end of the distribution, manifesting as the high prevalence of elevated ALT, calls for intensified clinical prevention.

The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR), a lipid-related biomarker, remains underexplored in relation to the risk of advanced fibrosis and hepatic steatosis. The present study aimed to investigate the potential association between the NHHR and these hepatic conditions. A total of 6,907 individuals aged 20 years and older from the National Health and Nutrition Examination Survey 2017-2020 were included in the present study. Advanced fibrosis and hepatic steatosis were assessed using hepatic vibration-controlled transient elastography. Multivariate regression analysis and subgroup analysis were performed to explore the independent association between the NHHR and the presence of advanced fibrosis and hepatic steatosis. Among the 6,907 adults included in the present study (mean age, 50.56±17.21 years; 3,398 male patients and 3,509 female patients), 409 (5.92%) were diagnosed with advanced fibrosis and 3,034 (43.93%) were diagnosed with hepatic steatosis. Following multivariable adjustment (age, sex, ethnicity, education level, family income-to-poverty ratio, smoking status, alcohol use and vigorous physical activity), logistic regression analysis demonstrated that an elevated NHHR was positively associated with increased possibility for advanced fibrosis [odds ratio (OR), 1.10; 95% confidence interval (CI), 1.03-1.17; P=0.005]. The restricted cubic spline model indicated a linear dose-response association between the NHHR and advanced fibrosis. The NHHR also exhibited a significant association with a higher risk of hepatic steatosis after full adjustment for covariates (OR, 1.61; 95% CI, 1.53-1.68; P<0.001). Using a two-segment linear regression model, an S-shaped relationship was identified between the NHHR and hepatic steatosis, with an inflection point at 3.83. In conclusion, the present study established a robust association of the NHHR with advanced fibrosis and hepatic steatosis. The NHHR may serve as a straightforward anthropometric index for predicting these conditions.

Relapse after radical treatment remains a major concern in hepatocellular carcinoma (HCC), affecting 50-75 % of early-stage cases within 5 years. Early recurrence prediction is a clinical unmet need. Circulating blood biomarkers could provide a minimally invasive approach to detect minimal residual disease (MRD) post-intervention. Although alpha-fetoprotein has been the primary biomarker in this setting, its MRD sensitivity is limited to 50-70 %. This systematic review aims to summarize available evidence regarding the clinical validity and potential utility of emerging circulating blood biomarkers for MRD detection in HCC patients.

We searched PubMed and Embase for peer-reviewed articles and abstracts published up to 2025, and ClinicalTrials.gov for ongoing trials on circulating blood biomarkers for MRD in HCC.

A total of 91 studies (74 with results and 17 ongoing, out of 2,386) were retrieved. We evaluated various blood biomarkers, including circulating DNA (cDNA, N = 24), circulating tumor cells (CTCs, N = 20), circulating RNA (cRNA, N = 8), and other miscellaneous (N = 22) for MRD detection in HCC. These biomarkers demonstrated encouraging results, albeit with notable heterogeneity. In particular, circulating tumor DNA (ctDNA) and CTCs stand as the most robust novel approaches, with 50-80 % sensitivity and specificity up to 94 %. Nonetheless, none of the 17 ongoing studies involve biomarker-driven intervention to prove clinical utility.

Novel circulating blood biomarkers are mature for MRD detection in HCC. However, variability in methodologies and results highlights the need for further validation. We encourage the investigation of CTCs and/or ctDNA in interventional trials to assess clinical utility. This biomarker-driven approach may enhance adjuvant treatment effectiveness in MRD-positive cases while minimizing toxicity in MRD-negative patients.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health problem. The secondary stage in MASLD is steatohepatitis (MASH), the co-existence of steatosis and inflammation, a leading cause of progression to fibrosis and mortality. MASH resolution alone improves survival. Currently, MASH diagnosis is via liver biopsy. This study sought to evaluate the accuracy of imaging-based tests for MASH diagnosis, which offer a non-invasive method of diagnosis.

Eight academic literature databases were searched and references of previous systematic reviews and included papers were checked for additional papers. Liver biopsy was used for reference standard.

We report on 69 imaging-based studies. There were 31 studies on MRI, 27 on ultrasound, five on CT, 13 on transient elastography, eight on controlled attenuation parameter (CAP) and two on scintigraphy. The pathological definition of MASH was inconsistent, making it difficult to compare studies. 55/69 studies (79.71%) were deemed high-risk of bias as they had no preset thresholds and no validation. The two largest groups of imaging papers were on MRI and ultrasound. AUROCs were up to 0.93 for MRE, 0.90 for MRI, 1.0 for magnetic resonance spectroscopy (MRS) and 0.94 for ultrasound-based studies.

Our study found that the most promising imaging tools are MRI techniques or ultrasound-based scores and confirmed there is potential to utilise these for MASH diagnosis. However, many publications are single studies without independent prospective validation. Without this, there is no clear imaging tool or score currently available that is reliably tested to diagnose MASH.

To compare the effects of ipragliflozin, a sodium-dependent glucose transporter-2 inhibitor, and those of metformin on the visceral fat area (VFA), a prospective, multi-centre, open-label, blinded-endpoint, randomized, controlled study was undertaken. The generated data were used to examine the effects of ipragliflozin and metformin on indices of hepatic steatosis and liver fibrosis.

In total, 103 Japanese patients with type-2 diabetes (T2D), body mass index (BMI) of ≥22 kg/m2 and glycated haemoglobin level of 7%-10% were randomly administered ipragliflozin 50 mg or metformin 1000 mg for 24 weeks. Various parameters, including hepatic steatosis indices, fatty liver index (FLI), hepatic steatosis index (HSI), non-alcoholic fatty liver disease-liver fat score (NAFLD-LFS), liver fibrosis indices, AST to platelet ratio index (APRI) and fibrosis-4 (FIB-4) index, were compared in the sub-analyses. The correlations between changes in each index and VFA were evaluated.

At baseline, patients demonstrated moderate hepatic steatosis, with FLI scores of 52.9 ± 26.6 and 57.8 ± 29.0 in the ipragliflozin and metformin groups, respectively. At 24 weeks, compared with metformin, ipragliflozin showed improvements in hepatic steatosis indices: FLI (-9.24 ± 10.7 vs. -3.45 ± 11.8, p = 0.013), HSI (-1.45 ± 2.32 vs. -0.45 ± 1.87, p = 0.021), NAFLD-LFS (-0.70 ± 1.46 vs. -0.04 ± 0.98, p = 0.011) and liver fibrosis index: APRI (-0.110 ± 0.323 vs. 0.033 ± 0.181, p = 0.010). In the ipragliflozin group, changes in FLI and HSI were correlated with VFA reduction (r = 0.340, p = 0.024; r = 0.367, p = 0.011, respectively).

Compared with metformin, ipragliflozin improved multiple hepatic steatosis and liver fibrosis indices, suggesting that ipragliflozin exerts potential hepatoprotective effects in early-stage liver disease associated with T2D.

Metabolic dysfunction-associated steatotic liver disease is a significant driver of the increasing global burden of chronic liver disease. This study aimed to describe the temporal trends and inequalities of liver complications related to metabolic dysfunction-associated steatotic liver disease (LC-MASLD) by geographical region, age and sex during 1990-2021.

Global Burden of Diseases Study 2021 data were analysed to assess LC-MASLD incidence, prevalence, mortality and disability-adjusted life years (DALYs). Temporal trends during 1990-2021 were measured by 'estimated annual percentage change' (EAPC). Inequalities of LC-MASLD burden across countries were evaluated by the slope index of inequality (SII) and the relative concentration index (RCI).

During 1990-2021, LC-MASLD rose annually by 0.73% in incidence and prevalence, 0.19% in mortality and 0.16% in DALYs. In 2021, the Middle East and North Africa had the highest incidence and prevalence and Andean and Central Latin America had the highest mortality and DALY rates. While LC-MASLD incidence was earliest in the 15-19 age group, both prevalence and DALY rates peaked at 75-79 years for both sexes. Inequalities in mortality and DALYs by countries' socioeconomic development index increased during 1990-2021, demonstrated by a decline in SII from -0.09 to -0.56 per 100 000 for mortality and from 1.41 to -7.74 per 100 000 for DALYs. RCI demonstrated similar findings.

The LC-MASLD burden is increasing globally, especially in economically disadvantaged countries, with widening disease inequalities during 1990-2021. Effective prevention and subregional interventions are crucial, with a specific focus on resource optimisation for disadvantaged populations.

Metabolic dysfunction-associated steatohepatitis (MASH) has become the dominant cause of liver disease in the United States. With the growing burden of this disease in gastroenterology practices, the identification and treatment of those at risk of developing adverse outcomes (cirrhosis, hepatocellular carcinoma, or liver-related death) has become urgent. In recent years, the development of noninvasive tests (NITs) to identify "at-risk MASH" patients have provided cost-effective algorithms to identify these patients. Although treatment has historically been limited to lifestyle modification, recent FDA approval of resmetirom for noncirrhosis MASH with stages 2 and 3 fibrosis has provided a new opportunity in the United States to provide these patients with novel treatment options. Other new effective treatment regimens are on the horizon. Given that gastroenterology and hepatology practices in the United States heavily rely on advanced practice providers (APPs) to manage patients with MASLD, the APP Committee of the Global NASH/MASH Council has curated the essentials of day-to-day MASH management for our busy gastrohepatology providers and their APP colleagues. The goal of this document is to equip and mobilize more GI providers with the requisite competencies for the management of at-risk MASH, given the rapidly evolving MASH treatment landscape.

Curative surgery for hepatocellular carcinoma (HCC) includes liver resection (LR) and orthotopic liver transplantation (OLT). Due to the obesity epidemic, metabolic dysfunction-associated steatotic liver disease (MASLD) is a frequent HCC aetiology that often coincides with increased alcohol consumption, termed MetALD, or even alcohol-associated liver disease (ALD).

Patients undergoing LR or OLT for HCC at Charité-Universitätsmedizin Berlin (2010-2020) were included in this retrospective cohort study investigating disease aetiology, time to recurrence (TTR), overall survival (OS) and CT-based body composition.

Out of 579 patients with HCC, 417 underwent LR and 162 OLT. Tumour aetiologies were viral n = 191 (33.0%), MASLD n = 158 (27.3%), MetALD n = 51 (8.8%), ALD n = 68 (11.7%) and other/cryptogenic n = 111 (19.2%). Patients with MASLD and MetALD had more intramuscular (p < 0.001, p = 0.015) and visceral fat (both p < 0.001) than patients with non-metabolic dysfunction aetiologies. Patients with MASLD-HCC had comparable TTR (median 26 months, [95% CI: 23-31] vs. 30 months [95% CI: 4-57], p = 0.425) but shorter OS than patients with other HCC aetiologies (63 months [95% CI: 42-84] vs. 80 months [95% CI: 60-100], hazard ratio: 1.53 [95% CI: 1.050-2.229], p = 0.026) after LR. Multivariate analysis confirmed MASLD aetiology, portal vein thrombosis and MELD score ≥ 10 as independent prognostic factors for OS in LR (adjusted p = 0.021,p < 0.001,p = 0.003), even after excluding in-hospital mortality (adjusted p = 0.016,p = 0.002,p = 0.002). Causes of death were similar in MASLD and non-MASLD aetiology.

Patients with HCC undergoing LR and meeting the new MASLD criteria have significantly shorter OS. This study provides empirical prognostic evidence for the novel MASLD/MetALD classification in a large European cohort of patients undergoing curative-intent HCC therapy.

Nonalcoholic fatty liver disease (NAFLD) manifests as chronic hepatic steatosis, occurring variably across people due to racial and genetic diversity. It represents a stage in the development of chronic liver disease, marked by fat accumulation, inflammatory responses, oxidative stress in the endoplasmic reticulum, and fibrosis as primary concerns. Understanding its underlying mechanisms remains a challenging and pivotal area of study. In the past, acute liver injury-related diseases were commonly treated with methods such as liver transplantation. However, the emergence of artificial liver has shifted focus to stem cell therapies. Unlike conventional drugs, stem cell therapies are continuously evolving. Despite being classified as drugs, stem cells demonstrated significant efficacy after multiple injections. Mesenchymal stem cells, unlike other types of stem cells, do not have the risk of tumor formation and low immunogenicity, reducing the hypersensitivity reactions associated with liver transplantation. Increasingly, studies suggest that mesenchymal stem cells hold promise in the treatment of chronic liver injury diseases. This review focuses on investigating the role of mesenchymal stem cells in chronic metabolic liver diseases, such as non-alcoholic fatty liver disease, and delves into their specific functions.

This study examines the link between serum manganese (Mn) levels and non-alcoholic fatty liver disease (NAFLD), with a focus on gender differences.

Utilizing data from the NHANES 2017-2018, we included participants aged 18 and older, excluding those without ultrasonic liver assessment, serum Mn data, or with hepatitis or significant alcohol use. The final analysis comprised 4,294 individuals, with 2,708 in the NAFLD group and 1,586 in the non-NAFLD group. Serum Mn was quantified via inductively coupled plasma mass spectrometry. We compared demographic and health-related variables between groups using appropriate statistical tests and categorized participants into quartiles based on Mn levels. Multivariate logistic regression and spline regression analyses were conducted to evaluate the association between serum Mn and NAFLD risk by gender.

Serum Mn was significantly elevated in the NAFLD group compared to non-NAFLD individuals (9.06 vs. 9.33 μg/L, Z = 2.815, p = 0.005). After adjustments, males in the third Mn quartile showed a higher NAFLD risk (OR = 1.575; 95% CI: 1.193-2.087), while females in the fourth quartile also had increased risk (OR = 1.725; 95% CI: 1.313-2.269), both compared to the first quartile (p < 0.01). A positive dose-response relationship was found for both genders (P for trend <0.01), with nonlinear associations in males (P for nonlinearity <0.01) and linear associations in females (P for nonlinearity = 0.818). Significant interactions with ethnicity in males and hypertension in females were also noted.

Higher serum Mn levels are significantly associated with increased NAFLD risk in both genders, highlighting the need for gender-specific considerations in future studies and clinical practices.

Aberrant DNA methylation can lead to the onset of pathological phenotypes and is increasingly being implicated in age-related metabolic diseases. In our preceding study we show that the heterozygous ablation of Pcyt2, the rate limiting enzyme in phosphatidylethanolamine (PE) synthesis, causes an age-dependent development of non-alcoholic steatohepatitis (NASH), and that treatment with the Pcyt2 substrate phosphonoethylamine (PEA) can attenuate phenotypic NASH pathologies. Here, we hypothesize that abnormal DNA methylation patterns underly the development of Pcyt2 + /- NASH. In this study, we conduct an epigenome-wide methylation analysis to characterize the differential methylation of Pcyt2 + /- livers and investigate whether the attenuation of NASH with PEA treatment is associated with changes in DNA methylation.

Pcyt2 + /- NASH liver experiences significant alterations in DNA methylation pattens relative to Pcyt2 + / + . Differentially methylated genes belong to pathways including PI3K-Akt signalling pathway, Foxo signalling pathway, oxidative phosphorylation and insulin signalling/secretion, indicating that epigenetic regulation underlies many of our previously established functional pathological mechanisms of Pcyt2 + /- NASH. Previously unidentified pathways during Pcyt2 deficiency are highlighted, such as cell cycle regulation and cellular senescence that may contribute to NASH development. Treatment with PEA dramatically attenuates aberrant total and protein-coding DNA methylation patterns by 96%. PEA treatment restored the methylation status of key genes involved in epigenetic modifications and induced differential methylation of genes associated with obesity and T2DM such as Adyc3, Celsr2, Fam63b.

The Pcyt2 + /- liver methylome and transcriptome is altered and likely underlies much of the pathology in Pcyt2 + /- NASH phenotype. The treatment with PEA significantly attenuates aberrant DNA methylation in Pcyt2 + /- liver and corrects the DNA methylation of genes involved in the pathogenesis of NASH, indicating its therapeutic potential. This analysis provides critical insight into the epigenetic basis of NASH pathophysiology and suggests diagnostic markers and therapeutic targets.

Nonalcoholic Fatty Liver Disease (NAFLD) is characterized by excessive lipid accumulation in hepatocytes and is closely associated with metabolic disturbances such as obesity, dyslipidemia, and insulin resistance. Despite its increasing prevalence and potential progression to severe liver conditions, there is currently no approved pharmaceutical intervention for NAFLD. Traditional Chinese Medicine (TCM) formulations, such as Xiaoyao San (XYS), have shown therapeutic efficacy in treating NAFLD, but the underlying mechanisms remain unclear. This study employed a multi-omics approach to elucidate the therapeutic mechanisms of XYS in NAFLD. A rat model of NAFLD was established using a high-fat diet (HFD). The chemical constituents of XYS were analyzed using UPLC-MS/MS. Transcriptomics and proteomics analyses were performed to identify potential biological targets and signaling pathways involved in the therapeutic effects of XYS. The results were validated using ELISA and Western blotting. UPLC-MS/MS identified 225 prototype chemical components of XYS in the blood. XYS significantly reduced body weight, liver index, and Lee's index in NAFLD model rats. It ameliorated HFD-induced hepatic steatosis, down-regulated serum levels of ALT, AST, GGT, TG, TC, LDL-C, FBG, IL-1β, IL-6, TNF-α, and ROS, and up-regulated HDL-C levels. Transcriptomics and proteomics analyses revealed that XYS modulated key signaling pathways, including cAMP, TGF-β, NF-κB, and necroptosis. Specifically, XYS down-regulated the expressions of NF-κB, p-NF-κB, FOXO1, TGF-β1, RIP3, and p-MLKL, while up-regulating cAMP, PKA, p-PKA, and PPARα. XYS improves NAFLD by regulating the cAMP/PKA-mediated PPARα, FOXO1, and NF-κB signaling pathways. This study provides a comprehensive understanding of the molecular mechanisms underlying the therapeutic effects of XYS in NAFLD and supports its potential as a novel therapeutic intervention for this condition.

Based on liver stiffness measurement by vibration controlled transient elastography (LSM by VCTE), the Agile 3+ and 4 are novel noninvasive scores that accurately identify advanced fibrosis (≥ F3) and cirrhosis (F4), respectively. We investigated and compared the Agile 3+ and 4 scores' performances in predicting adverse events to LSM alone, FIB-4 and Fibroscan-AST (FAST) score.

This retrospective analysis included NAFLD patients with LSM by VCTE and laboratory testing from a tertiary care center from 2013 to 2022. Adverse events were defined as major adverse liver outcomes (MALO), hepatocellular carcinoma, liver transplant, and death. MALO was defined as ascites, hepatic encephalopathy, or esophageal variceal bleeding. We used the Cox proportional hazard rate model and the Harrell's concordance (C) statistic to compare predictive performances.

733 total subjects with median follow-up of 27.0 months were included. Average age was 58.1 years and 32.8% had type 2 diabetes. Average alanine aminotransferase was 46.6 IU/L, aspartate aminotransferase: 34.5 IU/L, albumin: 4.4 g/dL, and platelets: 241.1 × 109/L. Fourteen subjects had 21 adverse outcomes, including 10 MALO, 5 HCC, 4 liver transplants, 3 progression of MELD score, and 6 deaths. Agile 3+ and 4 respectively had the highest C stats of 0.911 (C stat SE 0.028) and 0.909 (C stat SE 0.029) compared to LSM (C stat 0.857, C stat SE 0.045), FIB-4 (C stat 0.843, C stat SE 0.037) or FAST (C stat 0.703, C stat SE 0.085).

The Agile 3+ and 4 scores had the highest likelihood of accurately predicting adverse outcomes including MALO and death compared to LSM alone, FIB-4 or FAST score.

Liver fibrosis is the primary predictor of complications in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, there are currently no non-invasive prognostic tests to stratify patients at risk for hepatic fibrosis progression. This study aimed to explore whether plasma proteins could serve as non-invasive biomarkers for monitoring MASLD disease progression.

Blood plasma protein analysis was performed on samples from a long-term follow-up study of patients with MASLD with repeated liver biopsies. Over 1100 proteins covering a broad range of biological processes were analyzed using 13 Olink® Target 96 panels. Protein level changes were compared between the different time points and between patients with or without an increase in the liver fibrosis stage between the two biopsies.

Increased vascular endothelial growth factor A (VEGFA) plasma levels were significantly associated with liver fibrosis progression in patients with a histologically assessed increase in the fibrosis stage.

These findings suggest that the plasma protein VEGFA may be an effective biomarker for monitoring fibrosis progression in patients with MASLD.

Liver biopsy assessment by pathologists remains the gold standard for diagnosing metabolic dysfunction-associated steatotic liver disease (MASLD). Current automated image analysis tools for patient risk stratification are often proprietary or not applicable to whole slide images (WSIs). Here, we introduce "Liver-Quant," an open-source Python package for quantifying steatosis and fibrosis in liver WSIs.

Liver-Quant leverages colour and morphological features to measure Steatosis Proportionate Area (SPA) and Collagen Proportionate Area (CPA). We evaluated the method using an internal dataset of 414 WSIs from adult patients (Leeds Teaching Hospitals NHS Trust, 2016-2022) and an external public dataset (109 WSIs). Semi-quantitative scores were extracted from pathological reports. The Spearman rank coefficient (ρ) assessed correlations between computed SPA/CPA and pathologist scores.

Steatosis quantification showed a substantial correlation (ρ = 0.92), while fibrosis quantification yielded a moderate correlation (ρ = 0.51). We further investigated the impact of three staining dyes (Van Gieson (VG), Picro Sirius Red (PSR), and Masson's Trichrome (MTC)) on fibrosis quantification (n = 18). Stain normalisation yielded excellent agreement in CPA measurements across all three stains. Without normalisation, PSR achieved the strongest correlation with human scores (ρ = 0.9) followed by VG (ρ = 0.8) and MTC (ρ = 0.59). Finally, we explored the impact of apparent magnification on SPA and CPA. High-resolution images (0.25 or 0.50 μm per pixel (MPP)) were necessary for accurate SPA measurement, while lower resolution (10 MPP) sufficed for CPA measurements.

Liver-Quant offers an open-source solution for rapid and precise MASLD quantification in WSIs applicable to multiple histological stains.

Metabolic dysfunction leading to non-alcoholic fatty liver disease (NAFLD) exhibits distinct molecular and immune signatures that are influenced by factors like gut microbiota. The gut microbiome interacts with the liver via a bidirectional relationship with the gut-liver axis. Microbial metabolites, sirtuins, and immune responses are pivotal in different metabolic diseases. This extensive review explores the complex and multifaceted interrelationship between sirtuins and gut microbiota, highlighting their importance in health and disease, particularly metabolic dysfunction and hepatocellular carcinoma (HCC). Sirtuins (SIRTs), classified as a group of NAD+-dependent deacetylases, serve as crucial modulators of a wide spectrum of cellular functions, including metabolic pathways, the inflammatory response, and the process of senescence. Their subcellular localization and diverse functions link them to various health conditions, including NAFLD and cancer. Concurrently, the gut microbiota, comprising diverse microorganisms, significantly influences host metabolism and immune responses. Recent findings indicate that sirtuins modulate gut microbiota composition and function, while the microbiota can affect sirtuin activity. This bidirectional relationship is particularly relevant in metabolic disorders, where dysbiosis contributes to disease progression. The review highlights recent findings on the roles of specific sirtuins in maintaining gut health and their implications in metabolic dysfunction and HCC development. Understanding these interactions offers potential therapeutic avenues for managing diseases linked to metabolic dysregulation and liver pathology.